Structural and thermodynamic analysis of thrombin:suramin interaction in solution and crystal phases.
Biochim Biophys Acta
; 1794(6): 873-81, 2009 Jun.
Article
em En
| MEDLINE
| ID: mdl-19332154
ABSTRACT
Suramin is a hexasulfonated naphthylurea which has been recently characterized as a non-competitive inhibitor of human alpha-thrombin activity over fibrinogen, although its binding site and mode of interaction with the enzyme remain elusive. Here, we determined two X-ray structure of the thrombinsuramin complex, refined at 2.4 A resolution. While a single thrombinsuramin complex was found in the asymmetric unit cell of the crystal, some of the crystallographic contacts with symmetrically related molecules are mediated by both the enzyme and the ligand. Molecular dynamics simulations with the 11 complex demonstrate a large rearrangement of suramin in the complex, but with the protein scaffold and the more extensive protein-ligand regions keep unchanged. Small-angle X-ray scattering measurements at high micromolar concentration demonstrate a suramin-induced dimerization of the enzyme. These data indicating a dissimilar binding mode in the monomeric and oligomeric states, with a monomeric, 11 complex to be more likely to exist at the thrombin physiological, nanomolar concentration range. Collectively, close understanding on the structural basis for interaction is given which might establish a basis for design of suramin analogues targeting thrombin.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Suramina
/
Trombina
Idioma:
En
Revista:
Biochim Biophys Acta
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Brasil